Amide groups are common in biological molecules (e.g. peptide bonds), but thioamides are rare. Thioamide groups are found naturally in the copper-chelating compound methanobactin described in Methylosinus trichosporium OB3b (Kim et al., 2004). The antibiotic sulfinemycin, produced by Streptomyces albus NRRL 3384, has a primary thioamide S-oxide moiety (Lee et al., 1995). Thioamide compounds such as 2-ethyl-4-pyridinecarbothioamide (ethionamide) are important second-line drugs in the treatment of multi-drug resistant Mycobacterium tuberculosis and M. leprae (Schroeder et al., 2002; Shepard et al., 1985). Toxicity of thioamides in mammals and Mycobacterium spp. is dependent on metabolic activation of the compounds via sequential oxygenations of the thioamide sulfur atom by flavoprotein monooygenases or cytochromes P450 (Debarber et al., 2000; Wang et al., 2000; Porter and Neal, 1978). Thioamide S-oxides are not toxic without further oxygenation and investigators have proposed that thioamide S,S-dioxides (which have not been isolated) or further oxidized species exert the observed toxic effects (Vannelli et al., 2002; Hanzlik and Cashman, 1983; Porter and Neal, 1978). This activity results in elimination of the thioamide sulfur and formation of nitrile and/or amide derivatives (Vannelli et al., 2002; Debarber et al., 2000; Porter and Neal, 1978).
EtaA, a thioamide-oxidizing flavin monooxygenase in Mycobacterium tuberculosis, converted thiobenzamide to thiobenzamide S-oxide and benzamide (Vannelli et al., 2002). Ralstonia pickettii TA, which can grow using thioacetamide as a sole source of nitrogen and carbon (Dodge et al., 2006), converted thiobenzamide sequentially to thiobenzamide S-oxide, benzonitrile, and benzamide. Whole M. tuberculosis cells metabolized ethionamide similarly through the corresponding S-oxide, nitrile, and amide derivatives (Debarber et al., 2000). Sulfur eliminated from thiobenzamide by R. pickettii TA was detected in the medium as sulfur dioxide/sulfite. Release of sulfur at this oxidation state from thiobezamide S,S-dioxide, the proposed intermediate after thiobenzamide S-oxide, requires an additional two-electron oxidation. The mechanisms of this additional sulfur oxidation and benzonitrile formation are unknown.
The following is a text-format thiobenzamide degradation pathway map. The organism which can initiate the pathway is given, but other organisms may also carry out later steps. Follow the links for more information on compounds or reactions. This map is also available in graphic (5k) format.
Thiobenzamide
Ralstonia pickettii TA
Mycobacterium tuberculosis
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| ethionamide monooxygenase
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Thiobenzamide S-oxide
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| ethionamide monooxygenase
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[Thiobenzamide S,S-dioxide]
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| A
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Benzonitrile
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v
to the
Benzonitrile Pathway
Page Author(s): Rachael Long
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